U18666A inhibits regulation of intracellular cholesterol metabolism and neurotransmitter release in human neuroblastoma cells

D. M. Byers, J. M. Carter, S. M. Sparrow, H. W. Cook, N. D. Ridgway

Research output: Contribution to journalArticle

Abstract

Niemann-Pick type C disease (NPC) is an autosomal recessive, cholesterol storage disorder which leads to severe neurological impairment and death usuall)' within the second decade. In the present study, we have shown that 3-B-[(2-diethylamino)ethoxy] androst-5-en-17-one (U18666A) mimics many of the biochemical features of NPC in the human neuroblastoma cell line SKN-SH and its neuronal subclone SH-SY5Y. U18666A (0.2 pg/ml) specifically inhibited cholesterol esterification stimulated by low density lipoprotein (LDL) and sphingomyelinase, but not 25-hydroxycholesterol. U18666A also caused lysosomal accumulation of LDL-derived cholesterol and blocked LDLmediated suppression of LDL receptor levels. Treatment of phorbol esterdifferentiated SH-SYSY cells with 0.2 μg U18666A/ml for 18h inhibited potassium depolarization-induced release of [3H]norepinephrine by 75%, while neurotransmitter release evoked by the calcium ionophore A23187 was only inhibited by 30%. No effect of U18666A on cell morphology or levels of protein kinase C isoforms (α,δ) implicated in neurotransmitter release were observed. These results suggest that U18666A alters plasma membrane cholesterol which in turn may affect norepinephrine release primarily at the level of a voltage-gated calcium channel. By extension, impaired neurotransmitter signalling associated with altered cholesterol metabolism may be a feature of NPC.

Original languageEnglish (US)
Pages (from-to)A1096
JournalFASEB Journal
Volume11
Issue number9
StatePublished - Dec 1 1997

ASJC Scopus subject areas

  • Biotechnology
  • Biochemistry
  • Molecular Biology
  • Genetics

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